Reduced Kidney Function Is Associated with Increasing Red Blood Cell Folate Concentration and Changes in Folate Form Distributions (NHANES 2011-2018)

Abstract

Background: Current studies examining the effects of high concentrations of red blood cell (RBC) or serum folates assume that high folate concentrations are an indicator of high folic acid intakes, often ignoring the contributions of other homeostatic and biological processes, such as kidney function. Objective: The current study examined the relative contributions of declining kidney function, as measured by the risk of chronic kidney disease (CKD), and usual total folic acid intake on the concentrations of RBC folate and serum folate (total as well as individual folate forms). Design: Cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) collected in 2-year cycles were combined from 2011 to 2018. A total of 18,127 participants aged ≥16 years with available folate measures, kidney biomarker data (operationalized as a categorical CKD risk variable describing the risk of progression), and reliable dietary recall data were analyzed. Results: RBC folate concentrations increased as CKD risk increased: low risk, 1089 (95% CI: 1069, 1110) nmol/L; moderate risk, 1189 (95% CI: 1158, 1220) nmol/L; high risk, 1488 (95% CI: 1419, 1561) nmol/L; and highest risk, 1443 (95% CI: 1302, 1598) nmol/L (p < 0.0001). Similarly, serum total folate concentrations increased as CKD risk increased: low risk: 37.1 (95% CI: 26.3, 38.0) nmol/L; moderate risk: 40.2 (95% CI: 38.8, 41.7) nmol/L; high risk: 48.0 (95% CI: 44.3, 52.1) nmol/L; the highest Risk: 42.8 (95% CI: 37.8, 48.4) nmol/L (p < 0.0001). The modeled usual intake of folic acid showed no difference among CKD risk groups, with a population median of 225 (interquartile range: 108−390) µg/day. Conclusion: Both RBC and serum folate concentrations increased with declining kidney function without increased folic acid intake. When analyzing associations between folate concentrations and disease outcomes, researchers may want to consider the confounding role of kidney function.

Keywords: chronic kidney disease; folate concentration; folate metabolism; folic acid.

Figure 1

Red blood cell (RBC) folate concentrations, modeled folic acid usual intake, and RBC-to-serum total folate concentrations ratio by chronic kidney disease (CKD) risk group. CKD risk determined by eGFR and albuminuria stages as outlined by the Kidney Disease Improving Global Outcomes workgroup.

Figure 2

Percentage change in red blood cell (RBC) and serum folate concentrations, total and individual forms, between highest chronic kidney disease (CKD) risk and the low CKD Risk. Percent change of folate forms between the highest CKD Risk group and the low risk group (%), error bars represent the 95% CI for percentage change. CKD risk determined by eGFR and albuminuria stages as outlined by the Kidney Disease Improving Global Outcomes workgroup. Positive numbers indicate higher concentrations in the highest CKD risk group when compared to low risk group. The shaded gray areas represent the estimated percentage change in the overall population. Percentage change stratification by age and race/Hispanic origin are overlayed in color. (A) Percentage change in red blood cell (RBC) and serum total folate concentrations and RBC/serum ratio. Serum total folate is the sum of folate forms (5-methylTHF, non-methyl folate, folic acid) excluding MeFox. (B) Percentage change in individual serum folate forms. Non-methyl folate is the sum of 3 minor forms: THF, 5-formylTHF, and 5,10-methenylTHF. 5-methylTHF and non-methyl folates share the same y-axis scale, MeFox and UMFA share a separate y-axis scale.

Figure 3

Pathway for folate metabolism. Diagram depicting the metabolism of folic acid and food folates; ECGP: enriched cereal grain product; ECGP + RTE: enriched cereal grain product plus ready-to-eat cereals; ECGP + SUPP: enriched cereal grain product plus folic acid containing supplements; ECGP + RTE + SUPP: enriched cereal grain product plus ready-to eat cereals plus folic acid containing supplements. Folic acid and food folates are transported into the blood stream via the small intestine. The liver then aids in the biotransformation of food folates to 5-methylTHF where it is either stored via polyglutamylation or re-enters the bloodstream where it is circulated to peripheral tissues, including bone marrow where it is actively transported into red blood cells. Circulating blood folates are filtered in the kidney, where a portion is reabsorbed, and excess and reduced forms are excreted in the urine [19,24]. Created with BioRender.com (accessed on 26 January 2022).